B-cell chronic lymphocytic leukemia (B-CLL IntroductionThe tumor suppressor TP53 plays an important role in the control of key genes involved in the regulation of DNA repair, cell cycle, and apoptosis. 1,2 p53 is activated in response to DNA damage or other forms of stress, protecting cells from malignant transformation. This is the reason why p53 is frequently inactivated in human cancer. p53 is a short-lived protein, and its cellular level is controlled by the rate at which it is degraded. Although several U3 ubiquitin ligases have been implicated in p53 ubiquitylation and degradation, MDM2 appears to function as a master regulator of p53. 3,4 MDM2 not only facilitates p53 degradation, but it also binds p53 and inhibits its transcriptional activity. Therefore, inhibitors of p53-MDM2 binding are expected to stabilize and activate p53. Recently, the first potent and selective small-molecule antagonists of MDM2, the nutlins, have been shown to activate the p53 pathway in cancer cells with wild-type p53 in vitro and in vivo. 5 B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived CD5 ϩ B lymphocytes. 6 TP53 is mutated in only 5% to 10% of B-CLL cases at diagnosis, but in nearly 30% in chemotherapy-resistant tumors. TP53 mutation is associated with poor clinical outcome, shorter survival, and lack of response to therapy with purine nucleoside analogs or alkylating agents. [7][8][9][10][11] In fact, alterations in the TP53 gene are among the worst prognostic indicators for B-CLL. [12][13][14] Most of the chemotherapeutic drugs currently used induce cell cycle arrest or apoptosis through activation of p53, and p53 inactivation leads to chemoresistance. 1,2 Chemotherapeutic drugs, including purine analogs, topoisomerase inhibitors, and alkylating agents, have been shown to effectively increase p53 levels in B-CLL. 15,16 Thus, p53 activation is considered among the critical molecular events in chemotherapy-induced apoptosis in B-CLL cells. Although TP53 is mutated in only 5% to 10% of patients, the p53 pathway could be altered at a higher frequency, thus effectively attenuating p53 function. One of the mechanisms involved in p53 stabilization in response to DNA damage is its phosphorylation by ataxia telangiectasia mutated (ATM) protein. 1,2 Interestingly, ATM is inactivated in 10% to 20% of B-CLL cases, thus providing an alternative way to disable p53 function. [17][18][19][20] Tumors with alterations upstream of p53 would not respond adequately to genotoxic chemotherapeutics that act through the p53 pathway (eg, alkylating agents such as chlorambucil and cyclophosphamide; purine nucleosides such as fludarabine and cladribine; or topoisomerase inhibitors such as doxorubicin and mitoxantrone). Therefore, new therapies that overcome these For personal use only. on May 11, 2018. by guest www.bloodjournal.org From defects by acting directly on p53 stability may benefit these patients. Nutlins activate p53 by releasing it from MDM2-mediated negative control and thus compensate for d...

Purpose: Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) remain B-cell malignancies with limited therapeutic options. The present study investigates the in vitro and in vivo effect of the phospholipid ether edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) in MCL and CLL.Experimental Design: Several cell lines, patient-derived tumor cells, and xenografts in severe combined immunodeficient mice were used to examine the anti-MCL and anti-CLL activity of edelfosine. Furthermore, we analyzed the mechanism of action and drug biodistribution of edelfosine in MCL and CLL tumor-bearing severe combined immunodeficient mice.Results: Here, we have found that the phospholipid ether edelfosine was the most potent alkyllysophospholipid analogue in killing MCL and CLL cells, including patient-derived primary cells, while sparing normal resting lymphocytes. Alkyl-lysophospholipid analogues ranked edelfosine > perifosine ≫ erucylphosphocholine ≥ miltefosine in their capacity to elicit apoptosis in MCL and CLL cells. Edelfosine induced coclustering of Fas/CD95 death receptor and rafts in MCL and CLL cells. Edelfosine was taken up by malignant cells, whereas normal resting lymphocytes hardly incorporated the drug. Raft disruption by cholesterol depletion inhibited drug uptake, Fas/CD95 clustering, and edelfosine-induced apoptosis. Edelfosine oral administration showed a potent in vivo anticancer activity in MCL and CLL xenograft mouse models, and the drug accumulated dramatically and preferentially in the tumor.Conclusions: Our data indicate that edelfosine accumulates and kills MCL and CLL cells in a rather selective way, and set coclustering of Fas/CD95 and lipid rafts as a new framework in MCL and CLL therapy. Our data support a selective antitumor action of edelfosine. Clin Cancer Res; 16(7); 2046-54. ©2010 AACR.Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are two major B-cell-derived neoplasias for which current therapy is not satisfactory, leading in most cases to relapse and eventually to a fatal outcome. This lack of efficient therapy underscores the need for a continued search for novel chemotherapeutic agents. CLL is the most common adult leukemia and is characterized by the progressive accumulation of mature CD5 + B lymphocytes in the peripheral blood, bone marrow, and secondary lymphoid organs. New treatment combinations have incorporated the use of purine analogue (fludarabine)-based regimens together with monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52), leading to improved complete response rates and prolonged progression-free survival, but a long-term survival benefit has not been shown (1, 2). MCL is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in the overexpression of cyclin D1 in mature B